Hi-C Identifies Complex Genomic Rearrangements and TAD-Shuffling in Developmental Diseases
| Autor: | Wiebke Hülsemann, Sérgio B. Sousa, Seval Türkmen, Pedro Louro, Vera M. Kalscheuer, Martin Vingron, Anna Latos-Bielenska, Marius-Konstantin Klever, Stefan Mundlos, Manuel Holtgrewe, Andreas Dufke, Björn Fischer-Zirnsak, Malte Spielmann, Fabiola Quintero-Rivera, Martin A. Mensah, Rocio Acuna-Hidalgo, Verena Heinrich, Eunice Matoso, Ilina D. Pluym, Uirá Souto Melo, Monika Cohen, Robert Schöpflin |
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| Rok vydání: | 2020 |
| Předmět: |
Developmental Disabilities
Molecular Conformation Chromosomal translocation ectopic enhancer-promoter interactions Medical and Health Sciences cytogenetics Translocation Genetic Cohort Studies Chromosome conformation capture Chromosome Breakpoints Segmental Duplications Genomic 0302 clinical medicine Hi-C Chromosomes Human Genetics (clinical) Genetics & Heredity 0303 health sciences Genome SOX9 Transcription Factor Biological Sciences Phenotype Segmental Duplications chromosome conformation capture Human Biotechnology medicine.medical_specialty Translocation Locus (genetics) Computational biology topologically associating domains Biology Chromosomes Article 03 medical and health sciences Genetic neo-TAD gene misregulation Genetics medicine Humans developmental disorders 030304 developmental biology Genome Human Human Genome Breakpoint Cytogenetics Chromatin Assembly and Disassembly Genomic Human genome 030217 neurology & neurosurgery Comparative genomic hybridization |
| Zdroj: | Am J Hum Genet American journal of human genetics, vol 106, iss 6 |
| ISSN: | 0002-9297 |
| DOI: | 10.1016/j.ajhg.2020.04.016 |
| Popis: | Genome-wide analysis methods, such as array comparative genomic hybridization (CGH) and whole-genome sequencing (WGS), have greatly advanced the identification of structural variants (SVs) in the human genome. However, even with standard high-throughput sequencing techniques, complex rearrangements with multiple breakpoints are often difficult to resolve, and predicting their effects on gene expression and phenotype remains a challenge. Here, we address these problems by using high-throughput chromosome conformation capture (Hi-C) generated from cultured cells of nine individuals with developmental disorders (DDs). Three individuals had previously been identified as harboring duplications at the SOX9 locus and six had been identified with translocations. Hi-C resolved the positions of the duplications and was instructive in interpreting their distinct pathogenic effects, including the formation of new topologically associating domains (neo-TADs). Hi-C was very sensitive in detecting translocations, and it revealed previously unrecognized complex rearrangements at the breakpoints. In several cases, we observed the formation of fused-TADs promoting ectopic enhancer-promoter interactions that were likely to be involved in the disease pathology. In summary, we show that Hi-C is a sensible method for the detection of complex SVs in a clinical setting. The results help interpret the possible pathogenic effects of the SVs in individuals with DDs. |
| Databáze: | OpenAIRE |
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